The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors.
The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors.
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DOI：
10.1038/s41467-021-26526-y
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发表时间：
2021-11-01
影响因子：
16.6
通讯作者：
Ikura M
中科院分区：
文献类型：
--
作者：
Gebregiworgis T;Kano Y;St-Germain J;Radulovich N;Udaskin ML;Mentes A;Huang R;Poon BPK;He W;Valencia-Sama I;Robinson CM;Huestis M;Miao J;Yeh JJ;Zhang ZY;Irwin MS;Lee JE;Tsao MS;Raught B;Marshall CB;Ohh M;Ikura M
携带不同KRAS突变的癌细胞对SHP2抑制剂（SHP2i）表现出不同的敏感性。在这里，我们展示了携带KRAS Q61H的细胞对SHP2i具有独特的抗性，并利用生物物理学、分子动力学和基于细胞的方法研究了潜在的机制。Q61H突变会破坏GTP的内在水解和gap介导的GTP水解，并阻碍SOS1的激活，但不会改变酪氨酸磷酸化。野生型和Q61H突变型KRAS均被Src在Tyr32和Tyr64上磷酸化，并被SHP2去磷酸化，然而，SHP2i不降低KRAS Q61H细胞中ERK的磷酸化。与SHP2i敏感性相关的野生型和gly12突变型KRAS的磷酸化，赋予了对GAP和GEF活性调控的抗性，并削弱了与RAF的结合，而KRAS Q61H几乎完全的GAP/GEF抗性保持不变，并保留了高亲和力的RAF相互作用。SHP2可以通过调节GEF/GAP活性和KRAS去磷酸化来刺激KRAS信号传导，而这些过程无法调节Q61H突变体的信号传导。SHP2促进ras驱动的MAPK信号传导，但尚不清楚为什么具有不同KRAS突变的癌细胞对SHP2抑制表现出不同的敏感性。本文作者表明，KRAS Q61H与SHP2介导的上游调控脱钩，因此Q61H胰腺癌细胞维持MAPK信号传导，并且对SHP2抑制剂难以抑制。
Cancer cells bearing distinct KRAS mutations exhibit variable sensitivity to SHP2 inhibitors (SHP2i). Here we show that cells harboring KRAS Q61H are uniquely resistant to SHP2i, and investigate the underlying mechanisms using biophysics, molecular dynamics, and cell-based approaches. Q61H mutation impairs intrinsic and GAP-mediated GTP hydrolysis, and impedes activation by SOS1, but does not alter tyrosyl phosphorylation. Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. Phosphorylation of wild-type and Gly12-mutant KRAS, which are associated with sensitivity to SHP2i, confers resistance to regulation by GAP and GEF activities and impairs binding to RAF, whereas the near-complete GAP/GEF-resistance of KRAS Q61H remains unaltered, and high-affinity RAF interaction is retained. SHP2 can stimulate KRAS signaling by modulating GEF/GAP activities and dephosphorylating KRAS, processes that fail to regulate signaling of the Q61H mutant. SHP2 promotes RAS-driven MAPK signalling, but it is unclear why cancer cells with distinct KRAS mutations exhibit differential sensitivity to SHP2 inhibition. Here the authors show that KRAS Q61H is decoupled from SHP2- mediated upstream regulation, thus Q61H pancreatic cancer cells maintain MAPK signalling and are refractory to SHP2 inhibitors.
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影响因子：
82.9
作者：
Dardaei L;Wang HQ;Singh M;Fordjour P;Shaw KX;Yoda S;Kerr G;Yu K;Liang J;Cao Y;Chen Y;Lawrence MS;Langenbucher A;Gainor JF;Friboulet L;Dagogo-Jack I;Myers DT;Labrot E;Ruddy D;Parks M;Lee D;DiCecca RH;Moody S;Hao H;Mohseni M;LaMarche M;Williams J;Hoffmaster K;Caponigro G;Shaw AT;Hata AN;Benes CH;Li F;Engelman JA
通讯作者：
Engelman JA
影响因子：
28.2
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
通讯作者：
Tang KH
影响因子：
16.6
作者：
Chabon JJ;Simmons AD;Lovejoy AF;Esfahani MS;Newman AM;Haringsma HJ;Kurtz DM;Stehr H;Scherer F;Karlovich CA;Harding TC;Durkin KA;Otterson GA;Purcell WT;Camidge DR;Goldman JW;Sequist LV;Piotrowska Z;Wakelee HA;Neal JW;Alizadeh AA;Diehn M
通讯作者：
Diehn M
影响因子：
3.6
作者：
Bournet B;Muscari F;Buscail C;Assenat E;Barthet M;Hammel P;Selves J;Guimbaud R;Cordelier P;Buscail L
通讯作者：
Buscail L
影响因子：
8.8
作者：
Ahmed, Tamer A.;Adamopoulos, Christos;Poulikakos, Poulikos I.
通讯作者：
Poulikakos, Poulikos I.